Abstracts

Progesterone- and deoxycorticosterone-derived neuroactive steroids that positively modulate GABA[sub]A[/sub] receptors are potent anticonvulsants in animal models. Androstanediol (5[alpha]-androstan-3[alpha]-ol-17[beta]-diol) and androsterone (5[alpha]-androstan-3[alpha]-ol-17-one) are major metabolites of testosterone that also positively modulate GABA[sub]A[/sub] receptors. Recently, we have shown that androstanediol protects against seizures with potency lower than that of other neuroactive steroids. As of now, however, the possible anticonvulsant effects of androsterone have not been well characterized. Thus, we sought to determine the activity of this neuroactive steroid in whole animal and hippocampal slice seizure models. Male NIH Swiss mice were pretreated with androsterone and its protective effects were assessed in 6Hz and maximal electroshock (MES) models: corneal electrical stimulation (3 s, 32 mA, 6 Hz) and (0.2 s, 50 mA, 60 Hz), respectively. Additionally, pentylenetetrazol (PTZ) and pilocarpine seizure models were utilized. Androsterone-induced motor impairment was assessed in the inverted screen test. The ED[sub]50[/sub] (dose protecting 50% of animals), TD[sub]50[/sub] (dose producing motor impairment in 50% of animals) and protective index (PI) (PI = TD[sub]50[/sub]/ED[sub]50[/sub]) were determined.Epileptiform discharges in hippocampal slice, recorded as extracellular field potentials in CA3 region, were induced by perfusion with 4-aminopyridine (4-AP, 55 [mu]M). The effects of androsterone on 4-AP-induced discharges were studied in 10 min epochs during 1 hr recording. Androsterone protected mice from seizures with increasing rank of potencies in MES, pilocarpine, PTZ and 6 Hz models. The respective ED[sub]50[/sub] values were: 223.7 (182.5-274.1), 105.4 (47.7-232.7), 43.5 (31.6-60.0) and 29.1 (16.2-52.1) mg/kg. The TD[sub]50[/sub] value obtained in the inverted screen test was 152.3 (133.9-173.1) mg/kg. Accordingly, the respective PIs values were calculated: 0.68, 1.44, 3.5 and 5.23. Androsterone also inhibited epileptiform activity in hippocampal slices. At 100 [mu]M it almost completely blocked discharges induced by 4-AP. We have found that androsterone is a broad-spectrum anticonvulsant. Its anticonvulsant potency is higher than that of the other testosterone metabolite, androstanediol. These data, taken together, support a role of androsterone in regulation of seizure susceptibility and might open further investigations concerning the possible utility of this neuroactive metabolite of testosterone in the treatment of human epilepsy. (Supported by NINDS/NIH)